21 research outputs found
Molecular Mechanisms Underlying Vascular Liver Diseases: Focus on Thrombosis
No full textVascular liver disorders (VLDs) comprise a wide spectrum of clinical-pathological entities that primarily affect the hepatic vascular system of both cirrhotic and non-cirrhotic patients. VLDs more frequently involve the portal and the hepatic veins, as well as liver sinusoids, resulting in an imbalance of liver homeostasis with serious consequences, such as the development of portal hypertension and liver fibrosis. Surprisingly, many VLDs are characterized by a prothrombotic phenotype. The molecular mechanisms that cause thrombosis in VLD are only partially explained by the alteration in the Virchow's triad (hypercoagulability, blood stasis, and endothelial damage) and nowadays their pathogenesis is incompletely described and understood. Studies about this topic have been hampered by the low incidence of VLDs in the general population and by the absence of suitable animal models. Recently, the role of coagulation imbalance in liver disease has been postulated as one of the main mechanisms linked to fibrogenesis, so a novel interest in vascular alterations of the liver has been renewed. This review provides a detailed analysis of the current knowledge of molecular mechanisms of VLD. We also focus on the promising role of anticoagulation as a strategy to prevent liver complications and to improve the outcome of these patients
The New Era of Systemic Treatment for Hepatocellular Carcinoma: From the First Line to the Optimal Sequence
No full textHepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific risk factors, such as metabolic dysfunction-associated steatotic liver disease (MASLD), the incidence of HCC is growing globally, and mortality rates are still high. Moreover, patients frequently present at an intermediate or advanced tumor stage, when curative treatments, such as surgical resection, liver transplantation or ablation are no longer applicable. In these cases, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy are the only suitable options to achieve disease control. The multi-kinase inhibitor Sorafenib has been the only systemic treatment available for unresectable advanced HCC for almost a decade, but in the last couple of years new therapeutic options have emerged. Recent advances in understanding the interactions between the tumor and its microenvironment, especially cancer immune escape, led to the advent of immunotherapy. Currently, first-line systemic treatment for HCC is represented by the combination of the immune checkpoint inhibitor (ICI) Atezolizumab plus Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, but many other ICIs have been investigated, such as Nivolumab, Pembrolizumab, Durvalumab and Ipilimumab. However, the problem of second- and third-line therapies, and the correct sequence of treatments remains open and is not addressed in most studies. This explains the urge to find new systemic treatments that can improve the survival and quality of life in patients that can go beyond the first line of treatment. The aim of this paper is to offer a complete overview of the most recent innovations in systemic treatments for unresectable locally advanced and metastatic HCC, including emerging therapies, with a particular focus on treatment sequences. Moreover, we will provide an outlook on possible future approaches to patients who progress beyond first-line therapies
Cellular therapies in liver and pancreatic diseases
No full textOver the past two decades, developments in regenerative medicine in gastroenterology have been greatly enhanced by the application of stem cells, which can self-replicate and differentiate into any somatic cell. The discovery of induced pluripotent stem cells has opened remarkable perspectives on tissue re-generation, including their use as a bridge to transplantation or as supportive therapy in patients with organ failure. The improvements in DNA manipulation and gene editing strategies have also allowed to clarify the physiopathology and to correct the phenotype of several monogenic diseases, both in vivo and in vitro. Further progress has been made with the development of three-dimensional cultures, known as organoids, which have demonstrated morphological and functional complexity comparable to that of a miniature organ. Hence, owing to its protean applications and potential benefits, cell and organoid transplantation has become a hot topic for the management of gastrointestinal diseases. In this review, we describe current knowledge on cell therapies in hepatology and pancreatology, providing insight into their future applications in regenerative medicine.(c) 2022 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l
Non-Invasive Biomarkers for Immunotherapy in Patients with Hepatocellular Carcinoma: Current Knowledge and Future Perspectives
No full textThe treatment perspectives of advanced hepatocellular carcinoma (HCC) have deeply changed after the introduction of immunotherapy. The results in responders show improved survival compared with Sorafenib, but only one-third of patients achieve a significant benefit from treatment. As the tumor microenvironment exerts a central role in shaping the response to immunotherapy, the future goal of HCC treatment should be to identify a proxy of the hepatic tissue condition that is easy to use in clinical practice. Therefore, the search for biomarkers that are accurate in predicting prognosis will be the hot topic in the therapeutic management of HCC in the near future. Understanding the mechanisms of resistance to immunotherapy may expand the patient population that will benefit from it, and help researchers to find new combination regimens to improve patients’ outcomes. In this review, we describe the current knowledge on the prognostic non-invasive biomarkers related to treatment with immune checkpoint inhibitors, focusing on serological markers and gut microbiota
Microvascular Thrombosis and Liver Fibrosis Progression: Mechanisms and Clinical Applications
No full textFibrosis is an unavoidable consequence of chronic inflammation. Extracellular matrix deposition by fibroblasts, stimulated by multiple pathways, is the first step in the onset of chronic liver disease, and its propagation promotes liver dysfunction. At the same time, chronic liver disease is characterized by alterations in primary and secondary hemostasis but unlike previously thought, these changes are not associated with an increased risk of bleeding complications. In recent years, the role of coagulation imbalance has been postulated as one of the main mechanisms promoting hepatic fibrogenesis. In this review, we aim to investigate the function of microvascular thrombosis in the progression of liver disease and highlight the molecular and cellular networks linking hemostasis to fibrosis in this context. We analyze the predictive and prognostic role of coagulation products as biomarkers of liver decompensation (ascites, variceal hemorrhage, and hepatic encephalopathy) and liver-related mortality. Finally, we evaluate the current evidence on the application of antiplatelet and anticoagulant therapies for prophylaxis of hepatic decompensation or prevention of the progression of liver fibrosis
Management of Portal Hypertension in Patients with Hepatocellular Carcinoma on Systemic Treatment: Current Evidence and Future Perspectives
No full textSimple Summary Portal hypertension (PH) and hepatocellular carcinoma (HCC) are major complications of liver cirrhosis with a detrimental impact on patient outcomes that share common mechanisms. The incidence of PH in patients with advanced HCC is increasing due to the significant improvement of survival outcomes due to systemic therapies, so the management of the complications associated with clinically significant portal hypertension (such as variceal bleeding and ascites) becomes crucial. Moreover, the administration of systemic treatment presents challenges due to the drug-related bleeding risks. This review aims to elucidate the common pathophysiology of PH and HCC, with a specific focus on the influence of systemic therapies on PH. Moreover, we summarize the available evidence regarding PH management in HCC patients. Finally, we discuss potential new strategies for addressing the coexistence of CSPH and HCC.Abstract The management of CSPH in patients undergoing systemic treatment for HCC has emerged as a critical concern due to the absence of reliable diagnostic criteria and uncertainties surrounding therapeutic approaches. This review aims to underscore the primary pathophysiological aspects linking HCC and PH, while also addressing the current and emerging clinical strategies for the management of portal hypertension. A review of studies from January 2003 to June 2023 was conducted using the PubMed database and employing MeSH terms, such as "hepatocellular carcinoma", "immune checkpoint inhibitors", "systemic therapy", "portal hypertension", "variceal bleeding" and "tyrosine kinase inhibitors". Despite promising results of tyrosine kinase inhibitors in animal models for PH and fibrosis, only Sorafenib has demonstrated similar effects in human studies, whereas Lenvatinib appears to promote PH development. The impact of Atezolizumab/Bevacizumab on PH remains uncertain, with an increasing risk of bleeding related to Bevacizumab in patients with prior variceal hemorrhage. Given the absence of specific guidelines, endoscopic surveillance during treatment is advisable, and primary and secondary prophylaxis of variceal bleeding should adhere to the Baveno VII recommendations. Furthermore, in patients with advanced HCC, refinement of diagnostic criteria for CSPH and guidelines for its surveillance are warranted
Hepatocellular-Carcinoma-Derived Organoids: Innovation in Cancer Research
No full textHepatocellular carcinomas (HCCs) are highly heterogeneous malignancies. They are characterized by a peculiar tumor microenvironment and dense vascularization. The importance of signaling between immune cells, endothelial cells, and tumor cells leads to the difficult recapitulation of a reliable in vitro HCC model using the conventional two-dimensional cell cultures. The advent of three-dimensional organoid tumor technology has revolutionized our understanding of the pathogenesis and progression of several malignancies by faithfully replicating the original cancer genomic, epigenomic, and microenvironmental landscape. Organoids more closely mimic the in vivo environment and cell interactions, replicating factors such as the spatial organization of cell surface receptors and gene expression, and will probably become an important tool in the choice of therapies and the evaluation of tumor response to treatments. This review aimed to describe the ongoing and potential applications of organoids as an in vitro model for the study of HCC development, its interaction with the host's immunity, the analysis of drug sensitivity tests, and the current limits in this field
Durvalumab: an investigational agent for unresectable hepatocellular carcinoma
No full textIntroduction: Programmed death 1 (PD1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte associated protein 4 (CTLA-4) are proteins involved in the modulation of immune response, which are upregulated in hepatocellular carcinoma (HCC) tumor microenvironment (TME). Immune checkpoint inhibitors (ICIs) are a new class of drugs that counteract immunological tolerance to cancer cells. Despite the aggressiveness of HCC and its poor prognosis, only a few tyrosine kinase inhibitors (TKIs) and ICIs have been approved for patients with advanced disease. Areas Covered: We analyze the current knowledge on Durvalumab, a human antibody against PD-L1 its pharmacodynamics, and pharmacokinetics. We provide a description of its application in HCC, illustrating clinical trials that have demonstrated the safety and efficacy in this setting, either as monotherapy or in combination with other ICIs or TKIs, or as adjuvant treatment. Expert Opinion: Durvalumab is a promising drug that could extend the landscape of approved treatments for HCC. The clinical safety profile of Durvalumab was well manageable and comparable to other ICIs, with a low incidence of severe immune-related adverse events (irAEs). The importance of personalized therapy according to tumor characteristics is emerging, but very little is known about factors that could influence the efficacy of ICIs
The Crosstalk between Gut Microbiota, Intestinal Immunological Niche and Visceral Adipose Tissue as a New Model for the Pathogene-sis of Metabolic and Inflammatory Diseases: The Paradigm of Type 2 Diabetes Mellitus
No full textGut microbiota (GM) comprises more than one thousand microorganisms between bacterial species, viruses, fungi, and protozoa and represents the main actor of a wide net of molecular interactions, involving, among others, the endocrine system, immune responses, and metabolism. GM influences many endocrine functions, such as adrenal steroidogenesis, thyroid function, sexual hormones, IGF-1 pathway and peptides, produced in the gastrointestinal system. It is fundamental in glycaemic control and obesity, while also exerting an important function in modulating the immune system and associated inflammatory disease. The result of this crosstalk in gut mucosa is the formation of the intestinal immunological niche. Visceral adipose tissue (VAT) produces about 600 different peptides and it is involved in lipid and glucose metabolism, and some immune reactions, through several adipokines. GM and VAT interact in a bidirectional fashion: while gut dysbiosis can modify VAT adipokines and hormone secretion, VAT hyperpla-sia modifies GM composition. Acquired or genetic factors leading to gut dysbiosis or increasing VAT (i.e., Western diet) induce a pro-inflammatory condition, which plays a pivotal role in the development of dysmetabolic and immunologic conditions, such as diabetes mellitus. Diabetes is associated with specific patterns of GM alterations, an abun-dance or reduction of GM species involved in controlling mucosal barrier status, glycaemic levels and exerting a pro-or anti-inflammatory activity. All these factors could ex-plain the higher incidence of several inflammatory conditions in Western countries; fur-thermore, besides the specific alterations observed in diabetes, this paradigm could repre-sent a common pathway acting in many metabolic conditions and could pave the way to new, interesting therapeutic approaches
Liver Decompensation in Patients With Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab: A Real-life Study
No full textBackground & Aims: Atezolizumab plus bevacizumab (atezobeva) has changed the treatment landscape of advanced hepatocellular carcinoma, but its efficacy and safety in patients with impaired liver function are still debated. This study aimed to evaluate the prognostic impact of baseline liver function and liver decompensation during treatment on clinical outcomes. Methods: In this multicenter study, we included 247 patients with advanced or unresectable hepatocellular carcinoma treated with atezobeva. We analyzed data on survival, tumor progression, and liver decompensation and introduced time to decompensation as a new safety endpoint. Results: The reported overall survival (OS) was 18.30 months, time to progression 13.07 months, and progression-free survival (PFS) 9.83 months. Although OS was better in Child Pugh A compared with Child Pugh B patients (20.20 vs 9.83 months; P = .0008), no differences were observed in time to progression and treatment safety. Liver decompensation occurred in 63 patients (25.51%), specifically 27.89% Child Pugh A and 51.16% Child Pugh B patients; in 41.26% of patients, atezobeva was resumed after decompensation, achieving an OS comparable to those who never decompensated (20.87 vs 20.2 months; P = .77), and better than those who permanently stopped treatment (8.07 months; P = .02). Time to decompensation was similar for patients with albumin-bilirubin score 2 regardless of Child Pugh class, and the probability of recovery from decompensation was similar for Child Pugh A and B patients. Conclusion: Atezobeva is effective in both Child Pugh A and B patients. The possibility to resume treatment after an episode of decompensation underscores the importance of integrated hepato-oncological management
